6-fluoro-16alpha-methyl corticosteroids



United States Patent 3,291,815 6-FLUORO-16a-METHYL CORTICOSTEROIDS Ellis Rex Pinson, in, Jackson Heights, N.Y., assignor to Chas. Pfizer & (10., Inc., Brooklyn, N.Y., a corporation of Delaware No Drawing. Filed Aug. 26, 1959. Ser. No. 836,076 1 Claim. (Cl. 260-69145) This application is a continuation-in-part of my earlier filed copending US. application Serial Number 778,332, filed December 5, 1958, now abandoned.

The present invention is concerned with new and useful steroid compounds and to a procedure for producing them. More particularly, it is concerned with certain 16a-methyl pregnane derivatives and 21-esters thereof, to novel intermediates in the production thereof, and a process for the production of the novel compounds and the novel intermediates.

Although l6a-methyl pregnane derivatives are known, the 6a-fluoro and 6,8-fluoro-16wmethyl derivatives have not yet been reported.

Compounds of the character described in the present application possess valuable anti-inflammatory, anti-rheumatoid arthritic and glucocorticoid activities to a remarkable degree. The -6-fluoro-l6o -methylated corticosteroids of this invention have been found to possess these valuable therapeutic activities to a much higher degree than the heretofore available l6a-rnethylated corticosteroids and 16a-rnethylated-9wfiuoro-corticoster-oids.

These compounds are also useful in the treatment of inflammatory conditions of the skin, ears and eyes of humans and of valuable domestic animals as well as contact dermatitis and other allergic reactions. Compositions containing the valuable compounds of the present invention can be prepared for administration to humans or animals in conventional dosage forms such as pills, tablets, capsules, solutions, elixirs or syrups for oral use, or in liquid forms which are adaptable to the natural and synthetic cortical steroid hormones for injectable products. The novel steroids can also be administered topically in the form of ointments, creams, and the like.

The novel end products of this invention include those represented by the formula wherein B is selected from the group consisting of the carbonyl, a-hydroxymethylene and fi-hydroxymethylene radicals; X is selected from the group consisting of hydrogen, methoxyl, ethoxyl, halogen, especially fluorine; and the 21-acylates thereof wherein the acyl radical is that of a hydrocarbon carboxylic acid containing from 1 to 8 carbon atoms, inclusive. The configuration of the 6- fluoro atom may be on or B. Included also within the scope of this invention are the A -analogs corresponding to the above generic formula.

The process of the present invention for producing 6u-fiuoro-l6a-methyl steroids is illustrated by the following outline utilizing a A -pregnene derivative as starting material. It should be understood that although the out- 3,291,815 Patented Dec. 13, 1966 ice line refers to l6a-methylcortisone-21 acetate, the reactions are similarly applicable to other compounds represented by the above generic formula in which, of course, the 6-fluor-o group is absent. The term Ac represents an acyl radical of a hydrocarbon carboxylic acid containing from 1 to 8 carbon atoms, inclusive.

For the production of the 6B-fluoro-l Got-methyl steroids of the present invention, the same series of reactions are utilized except that the isomerization step is eliminated.

The invention includes also modifications of the process which comprises using as starting material a compound obtainable as an intermediate product at any stage of the process and carrying out the remaining process steps.

The process of the present invention for preparing 6afluoro-loa-methyl derivatives may be practiced in general by subjecting the appropriate l6a-methyl substituted corticosteroids, for example, l6a-methyl-A -pregnene-l7a,2l-diol-3,l1,20-trione-2l acetate (1) to hydrolysis to obtain the corresponding 2l-alcohol, followed by treatment with aqueous formaldehyde in the presence of a hydrogen halide to produce the BMD derivative of 16ot-methyl-A -pregnene-l7a,21-diol-3,l1,20 trione (II). Treatment of the thus produced BMD derivative with an alkylene glycol produces the 3-ketal of the A -steroid compound (III), which is then reduced with sodium borohydride to give the BMD derivative of l6ot-methyl-A pregnene 11B,17a,21-triol-3,20-dione 3 alkylene ketal (IV). Treatment of the thus produced llp-hydroxy-A pregnene with hydrogen peroxide or an organic peracid produces the corresponding highly useful 5a,6u-epoxide intermediate (V). Dehydration of the thus obtained 50:, 6zx-OXldO derivative at the 9,11 positions yields the BMD derivative of 5a,6a-oxido-16a-methyl-A -pregnene-l7, 2l-diol-3,20-dione-3-alky1ene glycol (VI) which on treatment with a fluorinating agent produces the corresponding Sa-hydroxy 6,B-fluoro halohydrin compound (VII). Removal of the protective BMD and ketal functions of the thus produced fluorohydrin is accomplished by treatment with acid to give 6,6-fluoro-l-6a-methyl- A -pregnene 50c,17ot,2l-iIlOl-3,20-dl0fl6 (VIII), which upon acetylation and dehydration yields 6 fi-fluoro-l6amethyl A4901) pregnadiene l7a,21-diol-3,20-dione-21 acetate (IX). Isomerization of the 6fi-fluoro derivative thus produced with a prototropic agent yields the fluoro-l6a-methyl-A -pregnadiene-l7a,21 diol-3,20- dione-Zl acetate (X). Treatment of the said 6a-fluoro compound with a hypohalogenating agent yields the 60- fluoro-Qa-halo-16ot-methyl-A -pregnene 11 fi,17oc,21-tfi0l- 3,20-dione-21 acetate (XI). Alternatively, the 6,8- fluoro-1'6a-methyl-A -pregnadiene-l7a,2l-diol 3,20

dione (IX) can be treated with a hyp'ohalogenating agent to produce the GB fiuOrO-9a-halo-l6a-methyl-A -pregnene- 11B,17u,21-triol-3,20-dione-21 acylate (XI). Isomerization of the said halohydrin-21 acylate produces the Getfluoro-9u-halo-l6a-methyl-A -pregnene 11,8,17a,21-triol- 3,20-dione-2l acylate (XI).

The said halohydrin derivative is then treated with an alkali acetate to produce the 9/3,11[3-oxido derivative (XII) which is then treated with a fluorinating agent to give the 9u-fluoro-11p-hydroxy compound (XIII), and thereafter hydrolyzed to the 6a,9a-difiuoro-loot-methyl- M-pregnene-llB,l7a,21-triol-3,20- dione. Oxidation of the 21-acylate of the said halohydrins (XI and XIII) yields the 6a-fluoro-9'a-halo-lGa-methyI-A -pregnene-17a, 2l-diol-3,11,20-triol-21 acetate (XIV which is then hydrolyzed in acid media to the corresponding 2l-alcohol. The halohydrin Zl-acylates (XI and XIII) can be dehydrogenated to give the corresponding 6a-fluoro-9u-halol6a-methyl-A -pregnadiene 1l6,l7a,21-triol-3,20-dione- 21 acylate (XV) and thereafter oxidized and hydrolyzed to give the corresponding 6a-fiuoro-9u-halo-16a-methyl- & A -pregnadiene-17a,21-diol-3,11,20--trione (XVI). Alternatively, the 6u-finoro-9a-halo-l6a-methyl-M-pregnene- 17a,21-diol-3,l1,20-trione-21 acylate (XIV) can likewise be dehydrogenated to the corresponding A -pregnadiene derivative (XVI).

The process of the present invention for producing Got-(or fl)-fluoro-16a-methyl corticosteroids having hydrogen in the 9-position and an oxygen containing group in the ll-position involves flnorination of compound V to give the valuable intermediate l7,20,20,2l-bisrnethylenedioxy 3 keto 511,115 dihydroxy 6,8 fluoro 16amethyl-allopregnane B-ethylene ketal, the compound analogous to compound VII wherein hydrogen and hydroxyl occupy the 9- and ll-positions, respectively. Application of reaction steps 8 through 11 of the reaction sequence produces XVII, 6a-fluoro-16u-methyl-hydrocortisone 21-acetate. Oxidation of the thus produced hydrocortisone 21-acetate derivative (XVII) gives the corresponding 6a-fiuoro-16a-methyl-cortisone 21-acetate (XVIII). Dehydrogenation of XVII and XVIII then produces the corresponding 6ot-fill0l'0-16OL-I1'1CthYI-PT6CI- nisolone and 6ot-fluoro-l6ot-methyl prednisone 21-acetates, respectively which are hydrolyzed to the 21-alcohols:

Alternatively, compound V can be oxidized to the corresponding valuable intermediate ll-keto compound which is then subjected to reaction steps 7 through 11 as outlined above for the corresponding llfi-hydroxy compound to give dot-fiuoro-16u-methyl-cortisone 21- acetate (XVIII). Reduction of the thus produced cortisone derivative produces the corresponding hydrocortisone derivative (XVII).

The process of the present invention for producing 6B-fiuoro-16u-methyl corticosteroids involves, as mentioned above, essentially the same reaction sequence with, of course, elimination of the isomerization step of the compound (IX).

It is an object of the present invention to provide novel Mot-methylated corticosteroids and the 2l-acylates thereof. A further object of this invention is to provide novel 6-fiuoro-16u-methylated corticosteroids and the 2l-acylates thereof. Still a further object of this invention is to provide novel intermediates of the 6- fluoro-lGa-methylated corticosteroids of the instant invention. Another object of the present invention is the provision of a process for the production of these novel 6-fluoro-16a-methylated corticosteroids and the intermediates thereof. Other objects will be apparent to those skilled in the art to which this invention pertains.

The 16u-methyl-A -pregnene-17,21-diol-3,11,20-trione- 21 acylate utilized in the first step of the above illustration of the valuable compounds of this invention, is prepared according to the procedure of Arth, et al., set forth in the I. Am. Chem. Soc., 80, page 3160, or according to the method described by Oliveto, et al., in the J. Am. Chem. Soc., 80, 4428. Other Mat-methylated steroids, such as, 1fia-methylhydrocortisone, l6tx-methyl-9efluorohydrocortisone, and 16a-methyl-9a-chlorohydrocortisone, which also may serve as starting materials for this reaction sequence are prepared according to the method of Arth, et al., described in the J. Am. Chem. Soc., 80, 3161.

In preparing the 6-fiuoro-9ot-alkoxy-1dot-methyl derivatives of the instant invention, the 9a-alkoxy substitnent can be introduced into the steroid nucleus by a modification of the above reaction sequence which comprises the acid catalyzed opening of the 918,115-oxide compound (XII) in the presence of a lower alcohol to give the 6-fluoro-9a-alkoXy-l6 8-methyl corticosteroid. 9e-alkoxy- 16a-methyl derivatives which may serve as starting materials for the preparation of the new compounds of this invention can be prepared by application of the methods described by Fried, et al., I. Am. Chem. Soc., 79, 1130 and by Arth, et al., I. Am. Chem. Soc., 80, 3160. Also, when it is desired to obtain 6-fluoro-16a-methyl corticosteroids bearing hydrogen in the 9-position, compound XI is dehalogenated by treatment with zinc in acetic acid.

In carrying out the process of the present invention, the 16e-methyl corticosteroid (I) is dissolved in a suitable solvent and hydrolyzed under mild acid or alkaline conditions. The reaction time is generally from a few hours to up to 3 days depending upon the particular compounds. In the preferred embodiment of this invention the 21-acylate is dissolved in chloroform and methanol and treated with hydrochloric acid of 20% to 37% concentration at room temperature. After several hours, the resulting 21-alcohol is isolated from the hydrolyzed mixture by evaporation under reduced pressure with simultaneous addition of water and, if desirable, purified by crystallization from a suitable organic solvent. The 21-alcohol is then converted to the hismethylenedioxy derivative (BMD) of the side-chain by combination with formaldehyde-hydrogen chloride or formaldehyde-hydrogen bromide at room temperature.

The reaction time is generally from 4 to 72 hours depending upon the compound being treated. Polymers of formaldehyde can also be used in place of aqueous formaldehyde but the formaldehyde-hydrogen chloride is the preferred reagent. In the preferred embodiment of this invention, the 21-alcohol is dissolved in methylene chloride and treated with equal volumes of 37% aqueous formaldehyde and of 37% hydrochloric acid and the two phase system stirred rapidly at room temperature for several hours. The methylene chloride which may be distilled oif during this period is replaced by about 4 to 6 volumes of hexane. The bismethylenedioxy derivative is then isolated by separating the two liquid phases, extracting the aqueous layer with a suitable organic solvent, such as, hexane, and washing the combined organic solutions repeatedly with Water. The organic solution is dried over anhydrous magnesium sulfate or other suitable drying agent, filtered and evaporated under reduced pressure to give the bisrnethylenedioxy derivative of the Ida-methyl corticosteroid (11).

The 1Sa-methyl-bismethylenedioxy derivative thus obtained is converted to the 3-alkylene ketal by reaction with a 1,2 or 1,3-glycol, such as, ethylene glycol 1,2- propanediol and 1,3-pr0panediol. In the preferred embodiment of this invention, the 16a-methyl-bismethylenedioxy derivative is mixed with. ethylene glycol, benzene and paratoluenesulfonic acid monohydrate and the mixture refluxed and stirred for several hours with contin nous removal of water. Upon completion of the reaction, the solution is cooled and made basic by addition of 5% aqueous sodium carbonate. The aqueous solution is extracted with a 1:1 benzene-ether solution, the organic layers separated, dried over a suitable drying agent, filtered and evaporated to give the corresponding 3-ketalized-A -pregnene compound (III). The 3-ketalized-ll keto 16a-methyl-A -pregnene-bismethylenedioxy derivative is reduced with a chemical carbonyl reducing agent, such as, sodium borohydride or lithium aluminum hydride, in an organic solvent to produce the corresponding 3-ketalized-llfl-hydroxyl-l6u-methyl-M-pregnene-bismethylenedioxy compound. In the preferred embodiment of this invention, the S-ketalized-ll-keto derivative is dissolved in ether and treated with an ethereal solution of sodium borohydride at reflux. Upon completion of this reaction, the reaction mixture is cautiously treated with Water or a dilute mineral acid to decompose excess sodium borohydride and organo-metal complexes. The product is isolated by filtration followed by evaporation of the solvent.

In carrying out the epoxidation step, the bismethylenedioxy derivative of the 3-ketalized-1lfi-hydroxyl-o pregnene compound is treated with a peracid such as, peracetic or per-benzoic acid or other known epoxidizing agent to product the 5a,6ot-epoxide. A mixture of both the uand B-oxides is produced in this epoxidation step and can be separated by chromatographic or crystallization techniques well known in the art. In the preferred embodiment of this invention, the bismethyllenedioxy derivative of the 3-ketalized-1lfi-hydroxyl-M-pregnene compound is dissolved in chloroform and treated with perbenz-oic acid at a temperature of about C. to C. for several hours followed by several hours at room temperature. The reaction mixture is then washed successively with 5% aqueous sodium bicarbonate and water. The chloroform layer is separated, dried over magnesium sulfate, filtered and evaporated to give the crude oxide mixture. Crystallization from methanol gives the desired 5u,6a-epoxide (V). The thus obtained 5a,6a-oxido-16amethyl compound is then dehydrated at the 9,11-positions with a suitable dehydrating agent, such as, methanesulfonytl chloride or paratoluene sul-fonyl chloride. In the preferred embodiment of the invention, a pyridine solution of the said 5a,6a-oxide under anhydrous conditions is treated with a pyridine solution of methanesulfonyl chloride at about 0 C. to 20 C. After one to four hours, the reaction mixture is allowed to come to room temperature. After several hours at room temperature the solution is added dropwise to cold water and the product, the 5a,6a-oxido-A -pregnene compound separated by filtration. It is recrystallized from a suitable organic solvent for purification.

The 5a,6a-oxido-A -p-regnene compound upon treatment with hydrogen fluoride or other fluorinating a-gents yields the corresponding 5a-hydroxyl-6B-fluoro compound (VII). The epoxide opening step can be performed under anhydrous or aqueous conditions in the presence or absence of a catalyst, such as, boron trifluoride. When anhydrous conditions are employed, a temperature of about 0 C. to 20 C. is generally employed. The use of anhydrous conditions does not remove'the 3-ketal or bismethylenedioxy functions whereas, aqueous conditions result in elimination of the 3-ketal function. The use of aqueous hydrofluoric acid also permits simultaneous removal of the bismethylenedioxy function to produce the Su-hydroxyl-6/3-fluoro-corticosteroid (VIII). The bismethylenedioxy derivative of the 6,8-fluoro-16tz-methyl- A -pregnen'e-5a,l7a,21-triol-3,20-dione 3-ethylene ketal obtained under anhydrous conditions is then hydrolyzed by means of aqueous acid,'such as, sulphuric acid, formic acid or acetic acid. In the preferred embodiment of the invention, it is preferred to reflux the bismethylenedioxy- S-ketalized derivative for a brief period, generally about to 30 minutes, in 60% formic acid. The crude 6B- fiuoro-l6a-methyl-5 oz,17on dihydroxy corticosteroid crystallizes upon the addition of water and concentration of the reaction mixture and is purified by recrystallization from a suitable organic solvent, such as, isopropyl ether.

In the preparation of the A -pregnadiene compound (IX), the 5ot-hydroxy-65-fluoro compound is dehydrated at the-4,5-positions in acid media. Suitable acid dehydrating agents include mineral acids, such as, hydrochloric acid and sulphuric acid. In addition, acetic acid, acetic anhydride and paratoluene sulfonic acid serve as suitable dehydrating agents. In the preferred embodiment of this invention, acid dehydration is employed, preferably in the presence of acetic or hydrochloric acid.

' The 6-fluoro-A -pregnadiene compound thus obtained consists essentially of the 6,8-fluoro-epi-mer. The 6a-epimer can be separated by chromatographic or crystallization techniques well known in the art. Conversion of the 6/8-epimer or of mixtures consisting essentially of the 6,8-epimer is accomplished by treatment of the 6-fluoro compound with a prototropic agent, such as, water, alcohols, organic acid-s and mineral acids. In the preferred embodiment of this invention the 6-fluoro compound, dissolved in chloroform and absolute methanol, is treated with anhydrous hydrogen chloride at --5 C. to 10 C. for about 3 hours. At the end of this period the reaction mixture is diluted with chloroform, washed successively with sodium bicarbonate and water and evaporated to dryness under reduced pressure. The 6a-fluoro b compound (X) is then recovered from the crude reaction product and purified by recrystallization.

It should be understood that the remaining reaction sequence applies equally well to the 6aor the 6B-fluoro compounds. The particular 6-fluoro sub-stituent used depends only on the final product desired. When, of course, the 6,8-fluoro epimer of the final product is desired, the isomerization step is omitted.

In carrying out the process of the present invention to produce 9a-halo-llfl-hydroxy derivatives (XI) the A steroid is dissolved in an inert organic solvent, such as dioxane, and reacted with a hypohalous acid such as, hypobromous or hypochlorous acid, or with a hypohalous acid releasing agent in the presence of an acid. Such hypohalous releasing agents include N bromo-acetamide, N-chlor-oacetamide, N-bromo-succinimide, N-iodosuccinimide, and N-chlorosuccinimide. Such agents permit the formation of a hypohalous acid in situ when treated with aqueous sulfuric acid, perchloric acid, and the like. The reaction is generally conducted at about room temperature using from equirnolar up to 25% excess of hypohalous acid releasing agent. At the completion of reaction, generally not over 2 hours, the excess of hypohalous acid is destroyed by the addition of sodium sulfite or hytposulfite. The 9a-halo-1lfl-hydroxy derivative thus produced is isolated by the addition of water followed by filtration of the precipitated product or extraction with an organic solvent. Purification is accomplished by recrystallization from a suitable organic solvent such as acetone. In the preferred embodiment of this invention the A G -pregnadiene derivative is dissolved in dioxane and perchloric acid solution at room temperature, and treated with solid N-bromoacetamide. The reaction mixture is protected from light and, after 1 hour, the excess perchloric acid is destroyed by the addition of aqueous sodium sulfite. The 9u-bromo-lli3-hydroxy halohydrin is isolated as described above and purified by recrystallization from acetone. The said halohydrin is then converted to the 9fi,11,6-oxide derivative by treatment with sodium or potassium acetate at room temperature for several hours. The epoxide is recovered by the addition of water followed by evaporation of the alcohol under reduced pressure and extraction of the aqueous solution with chloroform. The product is purified by recrystallization from a suitable organic solvent such as acetone.

Conversion of the 96,11,8-oxide to a halohydrin different from the foregoing halohydrin is accomplished by treatment with a halogenating agent such as, hydrogen halide, in a suitable organic solvent. The halogenating agent used may be the gaseous hydrogen halide, a concentrated aqueous solution, or a metal halide which releases hydrogen halide when treated with acids. The anhydrous hydrogen halides are generally preferred since they permit the use of temperatures ranging from 0 C. to 50 C. and relatively short reaction times. The product is recovered by neutralizing the excess hydrogen halide followed by extraction with water immiscible solvents, such as, methylene chloride and ethylene chloride. Evaporation of the organic solvent leaves the crude halohydrin which is purified by recrystallization from a suitable organic solvent. In the preferred embodiment of this invention the 913,1113-oxide is treated with hydrogen fluoride as described above. Hydrolysis under acid conditions of the 6,904 difluoro 16a methyl-M-pregnene-l15,17a,2ltriol-3,20-dione-2l-acetate (XIII) gives the desired 6,9ocdifiuoro 16a methyl A pregnene 11,8,17a,21 triol- 3,20-dione.

I In the oxidation of the 11,8-hydroxyl corticosteroid to the corresponding ll-keto compound, the llfi-hydroxyl compound is dissolved in a suitable organic solvent and treated with an oxidizing agent, such as, chromic acid, for a relatively brief period generally about, 15 to 60 minutes. In the preferred embodiment of this invention, an acetic acid solution of chromic acid is added to a solution of the ZI-acetate of the llB-hydroxy compound in glacial acetic 7 acid. After about a half-hour alcohol is added and the mixture concentrated to a syrup under reduced pressure. The desired ll-keto compound is isolated with chloroform and recrystallized from aqueous alcohol. Acid hydrolysis of the 2l-acetate of the ll-keto compound produces the 2l-alcohol.

The 6-fluoro-l1-oxygenated-l6a-methyl corticosteroids of this invention corresponding to Formula I, wherein X is hydrogen and B is selected from the group consisting of carbonyl and fi-hydroxymethylene, are produced by the fiuorination of the a,6.u-oxido-l6 x-methyl compound (V) as outlined above to give 17,20;20,2l-bismethylenedioxy 3 keto 5a,11[3 dihydroxy 65 fluoro 16amethylallopregnane 3-ethylene ketal. This valuable intermediate, or the precursor 5a,6a-oxido compound (V), can be oxidized to the corresponding ll-keto compound, if desired. In the preferred embodiment of this invention to produce 6-fiuoro-1l-oxygenated-16a-methyl corticosteroids, utilization of the 17,20;20,21-bismethylenedioxy- 3 keto 5a,11fi dihydroxy 65 fluoro 16a methyl allopregnane 3-ethylene ketal is favored.

The 5:2,115 dihydroxy 65 fluoro bismethylenedioxy compound is then hydrolyzed with 60% formic acid as as described above to remove the bismethylenedioxy and ketal functions to give 3,20-diketo-5a,l15,17a,21-tetrahydroxy-6B-fluoro-16a-methyl-a1lopregnane.

Acetylation of the thus produced allopregnane to the 2l-acetate followed by dehydration at the 4,5-positions as previously described produces fJ-fluoro-l6a-methyl- A pregnene l1 8,l7tx,21 triol 3,20-dione ZI-acetate. Isomerization of the oft-fiuoro compound, preferably with anhydrous hydrogen chloride as described above yields a-fluoro-lou-methyl-A -pregnene-l1,8,l7a,21-triol- 3,20-dione 21-acetate. Oxidation of the thus produced Goa-flLlOI'O compound produces 6u-fluoro-16a-methyl-A pregnene-17a,21-diol-3, l 1,20-trione 21-acetate.

Dehydrogenation of the llfi-hydroxy compounds or of the ll-keto compounds of this invention in the form of their 21-acetates to the A f-analogs is accomplished with excess selenium dioxide in a high boiling inert organic solvent such as, phenetole, diethylene glycol diether, dibutyl cellosolve, Xylene, dioxane, and so forth. A tertiary organic base may -be added to expedite reaction. In the preferred embodiment of this invention the steroid compound, dibutylcellosolve, a 10 molar excess of selenium dioxide and an equivalent molar quantity of pyridine are refluxed in an atmosphere of nitrogen for several hours. Upon completion of the reaction, the mixture is filtered tor decanted, evaporated in vacuo and the product isolated by crystallization from a suitable organic solvent or by chromatography on various adsorbents.

The order of the various steps outlined above can be varied considerably as will be recognized by those skilled in the art. For example, when 9tx-fluoro-16a-methyl- A -pregnene-17oz,21-diol-3,l1,20-trione 2l-acetate is utilized as starting material, the reaction sequence can proceed from compound V to VIII with elimination of step (6) and thence by acetylation and isomerization to the compound analogous to XIII. Choice of starting material thus determines the reaction sequence to be followed.

The following examples are given to illustrate the process and products of the present invention and are not to be construed as limiting.

EXAMPLE I 1 6a-methyl-A -pregnene-1 7a,21-dz'ol-3,11,ZO-trione To a suspension of 16a-methyl-A -pregnene-l7oc,21- diol-3,11,20-trione-2l acetate (450 g.) in chloroform (4.61), methanol (15.2 1.) and water (1.8 1.) is added 1.8 1. of concentrated hydrochloric acid. After 18 hours at room temperature the reaction mixture is concentrated under reduced pressure at 30 C. to 35 C. with simultaneous addition of water. The product, 16a-methyl-A pregnene-17a,21-diol-3,11,20-trione, is removed by filtration and used directly in the procedure of Example II.

If desired, the product may be recrystallized from alcohol.

EXAMPLE II 17,20;20,21bismethylenedi0xy-1 6 a-methyl-M- pregnene-3,1 1 -ai0ne The bismethylenedioxy derivative is prepared by dissolving 16a-methyl-n pregnene-l'7a,21-diol-3,11,20-trione (225 g.) in methylene chloride (1.5 1.) and treating with 37% aqueous formaldehyde (2.25 1.) and concentrated hydrochloric acid (2.25 l.) The two phase system is stirred rapidly at room temperature for 36 hours. During this period most of the methylene chloride distills oif and is replaced with hexane (12.5 1.). The two layers are separated, the aqueous acid layer extracted with onehalf its volume of hexane and the combined hexane solutions Washed with four separate portions of water in the proportions of volume water per volume of hexane solution. The hexane solution is dried over anhydrous magnesium sulfate, filtered and evaporated under re duced pressure to give the crude bismethylenedioxy derivative of 16a-methyl-A -pregnene-17a,21-dio1-3,11,20- trione. Recrystallization from methylene-chloride-methanol yields the pure product.

In the same manner, the following bismethylenedioxy (BMD) derivatives are prepared from the appropriate starting materials:

BMD 1'6u-methyl-A -epregnene-I1B,l7a,Zl-triol-3,20-dione BMD 9a-fluoro-l6a-tnethyl-A apregnene-11B,17a,21-triol- 3,20-dione BMD 9oz chloro-lGa-methyI-A pregnene-I1fl,17a,21-

triol-3,20-dione BMD 9'0: fluoro-16u-methyl-A -pregnene-17a,21-diol- 3 1 1 ,ZO-trione BMD 9a1rnethoxy-1Ga-methyl-M-pregnene-17a,21diol- 3,1 1,20-trione BMD 9m ethoxy-lu-methyl-M-pregnene-l 1;8,17a,21-

triol-3,20-dione BMD 91x bromo-16a-methyl-A -pregnene-l7a,2l-diol- 3,1 1,20-trione BMD 90c chloro-16u-methyl-A -pregnene-1704,2l-di0l- 3,1 1,20-trione BMD 9a ethoxy-l6a-metihyl-A -pregnene-17,2l-di01- 3,1 1,20-trione BMD 9oz methoxy-l6u-rnethyl-A -1pregnene-11fi,17a,21-

triol-3,20-dione BMD 9a bromo-lGa-methyI-M-pregnene-I1B,17u,21-

triol-3,2-0-dione EXAMPLE III 17,20,20,21-bismethylenedi0xy-16a-methyl-A -pregnene-3,11-dione 3-ethylene ketal BMD l6a-methyl-A apregnene-170:,21-diol-3,11,20-trione g), benzene (2.25 l.) and ethylene glycol (50 ml.) are thoroughly mixed and heated to remove a small amount of water by azeotropic distillation. Para toluene sulfonic acid monohydrate (5.0 :gr.) is added and the mixture stirred and refluxed for 20 hours with continuous removal of water. The mixture is then cooled, made basic by the addition of 5% aqueous sodium carbonate, and extracted with a 1:1 solution of benzene and ether. The organic layer is separated, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to give I G a-methyl-A regnene-17a,2l-diol- 3,11,20-trione 3-ethylene ketalbismethylenedioxy derivative.

Similarly, the following 3-ethylene ketals are prepared:

BMD l6a-trnethyl-A -pre1gnene-1lfi,17a,21-triol-3,20-di one 3-ethylene ketal BMD 90c =fluoro-1 6or-methyl-A -1pretgnene-l113,17 r,21-

triol-3,20-dione 3-ethylene ketal BMD 9oz chloro-l6amethyl-A -pregnened1,3,17a,21-

triol-3,20-d.ione 3-ethylene ketal BMD 90c fluoro-16a-methyl-A -pregnene-17a,21-diol- 3,11,20-tn'one S-ethylene ketal BMD 9a methoxy-16a-methyl-A pregnene-17a,2l-diol- 3,11,20-trione 3-ethylene ketal 1 BMD 9a ethoxy-16a-methyl-A -pregnene-11fi,17a,21-

triol-3,20-dione 3-ethylene ketal BMD 9oz bromo-16a-methyl-A -pregnene-17a,2l-diol- 3,11,20-trione 3-ethy-lene ketal BMD 9a chloro-l6a-methyl-A pregnene-17a,2l-diol- 3,11,20-trione 3-ethylene ketal BMD 9a ethoxy-16rx-methyl-A -pregnene-17a,21-diol- 3,11,20-trione 3-ethylene ketal BMD 9oz methoxy-16aethyl-A -tpre-gnene-l1B,17a,2l-

=triol-3,20-dione 3-ethylene ketal BMD 9a bromo-l6a-methyl-A pregnene-1lfl,17a,21-

trio1-3,20'dione 3-ethylene ketal EXAMPLE IV 17,20;20,21-bismethylenedioxy-I6a-methyl-A -pregnene-l1fi-0l-3-0ne-3-ethylene ketal To a solution of 16a-methyl-A -pre gnene-17a,21-diol- 3,11,20-trione 3-ethylene ketal-bistrn ethylenedioxy derivative (50 gms.) in anhydrous ether (22 l.) is gradually added a solution of sodium borohydride.(100 'gms.), ether (20 1.) over a period of about 2 hours. Water (2 l.) was then slowly added .and the ether phase separated. The aqueous phase is extracted with ethy-lacetate and the extract added to the ether phase. The combined etherethylacetate solution is washed with water, dried and evaporated to dryness under reduced 'pressure to give the BMD derivative of 16 otmethyl-A -prelgnene-116,1711,- 21-triol-3,20-di=one 3-ethylene ketal.

Similarly, the following 11/3-hydroxy derivatives are prepared: 1

BMD 9oz fluoro-l6a-methyl-A -pregnene-11B,17a,21-

triol-3,20-dione 3ethylene ketal BMD 9a methoxy-l6a-methyl-A -pregnene-1118,17 (1,21-

triol-3,20-dioue 3-ethylene ketal BMD 9a ethoxy-16mmethyl-A -pregnene-115,111,21-

triol-3,20 iione 3-ethylene ketal BMD 9a brcmo-l6zx-methyl-A -pre1gnene-11fl,17a,21-

triol-3,20-dione B-ethylene ketal BMD 90c chloro-l6u-methyl-A -pregnene-11 3,17a,21-

triol-3,20-dione B-ethylene ketal EXAMPLE V 1 7,20,20,21-bismethylenedixy-3-ket0-5a,6a-0xido-1 1 6- hydroxy-] 6a-methylallopregnane 3-ethylene ketal To a solution of the bismethylenedioxy derivative of 160: methyl-A -pregnene-11B,17a,21-triol-3,20-dione 3- ethylene ketal (75 -g.) in chloroform (1.5 l.) is added a chilled solution of 'perbenzoic acid (28.5 g.) dissolved in chloroform (475 1111.). After 24 hours at about 5 C. followed by 72 hours at room temperature, the solution is washed with 5% aqueous sodium bicarbonate and then with water. The chloroform layer is separated, dried and evaporated to give the crude epoxide. Recrystallization from methanol gives pure 5a,6a-oxido-16a-methyl- 11fl,l7a,21 trihydroxy-allopregnane-3,20-dione 3-ethylene ketal bismethylenedioxy derivative.

In like manner, the following 5u,6a-e1poxides are prepared from the appropriate A -pregnene derivative:

BMD 5a,6u oxido-9a-f1-uoro-16a-methyl-11 3,17a,21- trihydroxy-allopregnane-3,ZO-dione S-ethylene ketal BMD 511,60; oxido-9a-chloro-lGot-methyl-11B,17u,21- trihydroxy-allopregnane-3,ZO-dione 3-ethylene ketal BMD 506,6d-OXld0-9oL-1Tl6th0XY-16ot-mfithyl-l1B,17ot,2-1

tribydroxy-allopregnane-S,ZO-dione 3-ethylene ketal BMD 5a,6a oxido-9a-ethoxy-16a-methy1-11,8,17a,21- tiihydroxy-allopregnane-3,20-dione 3-ethylene ketal 10 BMD 5a,6oc oxido-9u-bromo-16a-methyl-11,8,17a,2ltrihydroxy-allopregnane-3,20-dione B-ethylene ketal BMD 50:,6oc oxido-16u-methyl-l7a,2l-dihydroxy-allopre.gnane-3,11,20-trione 3-ethylene ketal BMD 50,6oa oxido 9a-fluoro-16a-methyl-17a,2l-dihydroxy-a1lopregnane-3,11,20-trione 3-ethylene ketal BMD 50,6u oxido-9a-chlorc-16ot-methyl-17a,2l-dihydroxy-allopregnane-3,11,20-trione 3-ethylene ketal BMD 501,60; oxido-9a bromo-16a-methyl-17a,21-dihydroxy-allopregnane-3,11,20-trione 3-ethylene ketal BMD 50:,6oc oxido-9wmethoxy-16u-methyl-17a,21-dihydroxy-allopregu-ane-3,11,20-trione 3-ethylene ketal BMD 50;,60; OXidO-9oc-61ZhOXYl-l6oz-methyll7a,2l-di hydroxy-allopregnane-3,11,20-trione 3-ethyle-ne ketal EXAMPLE VI 17,20;20,21-bismethylenedioxy-5a,6a-0xid0-16u-methyl-A -pregnene-3-one-3-ethylene ketal To a solution of the bismethylenedioxy derivative of 50:,6oc oxido16 x-methyl-11,8,170:,21-trihydroxy-allopregname-3,20-dione 3ethylene ketal (55 g.) in anhydrous pyridine (600 ml.) cooled to 0 C., and protected from atmospheric moisture, is added a solution of methane sulfonyl chloride (51.5 ml.) in chloroform ml). After about one hour at 0 C., the mixture is allowed to come to room temperature and left standing for ten hours. The solution is then added dropwise to 5.5 l. of ice water with stirring to precipitate the bismethylenedioxy derivative of 5oz,6a oxido-l6a-methyl-A -pregnene- 17a,21-diol-3,20-dione 3-eflhylene ketal. The product is recovered by filtration, dried and recrystallized .from ethyl acetate.

EXAMPLE 1 7,20,20,21-bismetl ylene dioxy-6/3-flu0r0-16ot-methyl- A -pregnene-5a-0l-3-0ne 3-ethylene ketal Into each of four polyethylene bottles containing a solution of the bismethylenedioxy derivative of Su,6 xoxido-16a-methyl-A -pregnene-17a,2l-diol-3,20 dione B-ethylene ketal (9.2 g.) at 0 C. to 5 C. in methylene chloride m1.) is passed anhydrous hydrogen fluoride (20 g.). After vigorous stirring for two hours, the combined reaction mixtures'are evaporated to dryness to give the crude bismethylenedioxy derivative of 6/3-fluoro-16amethyl-M -pregnene-5a,17a,21-triol-3,20 dione 3-ethylene ketal.

The following fluorohydrins are prepared in the same manner: I

1 1 EXAMPLE VIII-A 6 fi-fluoro-l 6a-methyl-A -pregnene-5a,1 711,21 -tril- 3,2 O-dione To a solution of the bismethylenedioxy derivative of a,6oc-cxido-16a-methyl-A -pregnene-17a,21-di-ol 3,20- dione 3-ethylene ketal (5.2 g.) in methylene chloride (75 ml.) contained in a polyethylene beaker is added 25 ml. of 48% aqueous hydrofluoric acid. After vigorous stirring, at room temperature for one hour, the reaction mixture is poured into 750 ml. of water. To efiect complete removal of the ketal and bismethylenedioxy functions the aqueous organic system is heated to remove the methylene chloride. The remaining aqueous acid solution is heated to boiling for one-half hour and then concentrated under reduced pressure. The crude 6;3-fluoro-16a-methyl- A -pregnene-Sa,17a,21-triol-3,20-dione which separates is recrystallized from isopropyl ether.

EXAMPLE VIII-B Alternatively, the product of Example VII, the bismethylenedioxy derivative of 613-1111010-16oc-1'1'l6ihyl-A pregnene-5a,17ot,2l-triol-3,ZO-dione 3-ethylene ketal (25 g.) is refluxed for approximately 30 minutes in 60% formic acid (1.25 1.). Water (750 ml.) is then added and the solution concentrated at room temperature under reduced pressure. The 6fi-fluoro-16e-methyl-A pregnene-5a,17u,21-triol-3,20-dione which separates is purified by recrystallization from isopropyl ether. The product is identical to that of Example VIII-A.

Hydrolysis of the products of Example VII produces the following compounds.

63,9a-difluoro-16e-methy1-5a,11fl,17a,21-tetrahydroxyallopregnane-3 ,20-dione 6,8-fiuoro-9a-brorno-16a-methyl-5u,1 1B,17a,21-tetrahydroxy-allopregnane-3 ,20-dione 6fl-fluoro-9a-methoxy-16a-methyl-5 a,1 1p, 170:,2 1 -tetrahydroxy-allopregnane-3 ,ZO-dione 6/3-fluoro-9a-ethoxy- 16a-methyl-5 11,1 1fl,17ot,21-tetrahydroxy-allopregnane-3 ,20dione Git-fluoro-1Ga-methyl-Sm,17a,2l-trihydroxy-allopregnane- 3 ,1 1,20-trione 6,8-fluoro-9a-chloro-16u-rnethyl-5 x,17cc,2 l-trihydroxyallopregnane-3,1 1,20-trione 6fl-fiuoro-9u-bromo-16oc-methyl-5u,17a,21-trihydroxyallopregnane-3 1 1,20-trio ne 6,8-fiuoro-9m-methoxy-1 Ga-methyI-Sa,17a-,21-trihydroxyallopregnane-3 ,1 1,20-trione 6B-f1uoro-9ot-ethoxy-16w-methyl-5a,17a,21-trihydroxyal1opregnane-3 ,1 1,20-trione EXAMPLE IX The 6 8-fluoro-1Ga-methyl-A pregnene 5a,17c,21 triol-3,20-di-one (15 g.) is acetylated to the 2l-acetate with acetic anhydride in anhydrous pyridine according to standard procedures. The dry 21-acetate g.) is dissolved in acetic acid (500 ml.) and water (1.0 ml.), refluxed for one hour, then cooled, diluted with 500 ml. of water and evaporated to dryness under reduced pressure. The residue of fi-fluoro-l6umethyl-A -pregnadiene-17a, 21-diol-3,20-dione-21 acetate is used directly in the following example.

In like manner, the following 6B-fluoro-16oc-methyl- A -pregnene compounds are prepared from the products of Example VIII-13:

6fl,9a-difiuoro-16oL-methyl-A -pregnene-11;3,17a,21-triol- 3,20-dione-21-acetate 6t3-fluoro-9u-chloro-l6a-methyl-A -pregnene-1 1fi,17a,21-

triol-3,20-dione 21-acetate 6p-fluoro-9ot-bromo-l6ot-methyl-A -pregnene-1 1 13,17 0:,21-

triol-3,20-dione 21-acetate 6p-fiuoro-9a-methoxy-16a-methyl-A -pregnene-1 18.170,

21-triol-3,20-dione 21-acetate EXAMPLE X 6au0r0-16a-methyl-A -pregnadiene-17u,21-

dial-3,20-dione-21-acetate Into a solution of Gfi-fluoro-lGe-methyI-M -pregnadiene-17a,21-diol-3,20-dione-21-acetate (10 g.) in chloroform (850 ml.) and absolute alcohol (7 ml.) at 5 C. to -10 C., a stream of anhydrous hydrochloric acid is bubbled for about 3 hours. At the end of this period, the solution is diluted with chloroform (1.5 1.), washed successively with sodium bicarbonate and water, dried and evaporated to dryness under reduced pressure at 35-45" C. The residue, 6a-fluoro-16a-methyl-A -pregnadiene-17a,21-dio1-3,20-dione 21-acetate is recrystallized from acetoneSkellysolve B.

The following 6u-fluoro epirners are prepared in the same manner.

6a,9 x-difluoro-l 6a-methyl-A -pregnene-1 1B,17a,21-

triol-3,20-dione 21-acetate 6a-fluoro-9a-chloro-16a-methyl-A -pregnene-1 113, ;,2 1-

trio1-3,20-dione 21-acetate 6a-fluoro-9a-bromo-16ct-methyl-A -pregnene-1 1,3,17a,21-

triol-3,20-dione 21-acetate 6u-fluoro-9a-methoxy-16u-methyl-A -pregnene- 1 1 8,17a,21-trio1-3,20-dione 21-acetate 6a-fluoro-16a-methyl-A -pregnene-Sa, 170:,21-

triol-3,20-dione 21-acetate 6a-fluoro-9a-ethoxy- 1 6a-methyl-A -pregnene- 1 113,17a,12-triol-3,2O-dione 21-acetatefiu-fluoro- 16a-methyl-A -pregnene-1 1,6, l7oz,21-tri0l- 3 ,20-dione 2 l-acetate 6a-fluoro-16a-methyl-A -pregnene-17u,21-diol-3,1 1,20-

trione ZI-acetate 6a,9a-difluoro-16ot-methyl-A -pregnene-17a,2l-diol- 3 ,1 1,20-trione 21-acetate 6a-flu0ro-9a-chloro-16a-methyl-A -pregnene-17a,21-

diol-3, 1 1,20-trione 2 l-acetate 6ot-fluoro-9oz-bromo-16oz-methy1-A -pregnene-170:,21-

dio1-3, 11,20-trione 21-acetate 6a-fiuoro-9a-methoxy-16a-methyl-A -pregnene-1711,21-

diol-3,1 1,20-trione 21-acetate 6oc-fluoro-9a-ethoXy-16a-methyl-A -pregnene-1711,21-

diol-3 1 1,20-trione 21-acetate Hydrolysis of the 21-acetates of Examples IX and X, according to the procedure of Example I, produces the corresponding 21-alcohols.

Although in the following procedures the compounds are listed as 6-fiuoro compounds, it is understood that both the 6mand the 65- compounds are prepared. The appropriate 6ozor 6/8- compounds prepared as described above is employed as starting material.

EXAMPLE XI Solid N-bromoacetamide (3.8 g.) is added with stirring to a suspension of 6-fiuoro-16a-methyl-A -pregnadiene-l7a,21-diol-3,20-dione (8 g.) and 0.46 N perchloric acid (12 ml.) in peroxide-free dioxane (300 ml.) at room temperature over a period of about one hour. The reaction mixture is protected from light during the addition and for an additional hour. aqueous sodium sulfite is added with stirring until KI-starch paper no longer turns blue. Ice (350 g.) and chloroform (825 ml.) is added and the layers separated. The chloroform dioxane solution is washed with water, then concentrated to a syrup in vacuo at room temperature. acetone (350 ml.) to the syrup causes rapid crystallization. The mixture is chilled overnight then filtered. Ad ditional product is recovered from the filtrate by evaporation to dryness. Recrystallization from acetone gives pure 6 fiuoro 9a bromo 16a methyl A pregnene- 11,8,17a,21-triol-3,20-dione. Acetylation with acetic anhydride in pyridine gives the 2l-acetate.

In like manner the following 9a-halo-l lfi-hydroxy halohydrin derivative is prepared:

EXAMPLE XII A solution of 6-fiuoro-9u-bromo-l6a-methyl-A -preg nene-l1B,17a,21-triol-3,20-dione-2l-acetate (8 g.) in dioxane (260 ml.) is added to a solution of anhydrous potassium acetate (5.5 g.) in absolute alcohol (55 ml.) heated to near reflux temperature. The mixture is heated to The addition of 14 EXAMPLE XIV 6,9oc-difluOr0-1 6 a-methyl-A -pregnene-I 711,21

di0l-3 ,1 1,20-tri0ne 6,9 difluoro 16a methyl A pregnene 115,170, 21-triol-3,20-dione-21-acetate (0.5 g.) is oxidized in glacial acetic acid (12 ml.) with chromium trioxide (0.2 g.) in 50% aqueous acetic acid at about 12 C. to 15 C. for approximately minutes. The mixture is poured into water (100 ml.), neutralized with sodium bicarbonate to give crude 6,9u-difluoro-16a-methyl-A -pregnene-170:,21- diol-3,11,20-trione-21-acetate. Hydrolysis of the 21-acetate according to the procedure of Example I gives the 6,90 difiuoro 16oz methyl A pregnene 170:,21 diol- 3,11,20-trione. Oxidation of 6,9a-difluoro-16a-methyl- M-pregnene-l1B,17a,2ltriol-3,20-dione 21 acetate, the product of Example XVII, according to this procedure gives the same product.

The following 6-fi110I'O-9a-l18l0 corticosteroids are prepared in the same manner from the appropriate lip-hydroxy compound:

diol-3,1 1,20-trione 6-fiuoro-16a-methyl-A -pregnene-1704,2l-diol-3 ,11,20-

trione 6-fluoro-9a-ethoxy-16a-methyl-A -pregnene-17u,21'-

diol-3 ,11,20-trione l7,20;20,2 l bismethylenedioxy-3 ,1 l-diketo-S ot-hydroxy- 6,8-fiuoro-16a-methylallopregnane-3ethylene ketal 17 ,20;20,2 1 -bismethylenedioxy-3 ,11-diketo-5a-hydroxy- 613,9ot-difiuor0-16a-methyl-allopregnane-3 ethylene ketal 17,20;20,2 1 -bismethylenedioxy-3 ,1 1-diketo-5a-hydroxy- 6Bfluoro-9a-chloro-16a-methyl-allopregnane-3-ethylene ketal 1,7,20;20,'21-bismethylenedioXy-3 ,1 l-diketo-S a-bydroxyreflux for about minutes and then cooled rapidly. The

product, 6 fiuoro-9[3,l1;8-oxido-16a-methyl-A -pregnene- 17a,21-diol-3,20-dione-2l-acetate, is precipitated by the addition of ice-water and filtered. Concentration of the filtrate permits isolation of additional product. The same product-is obtained when the corresponding 9a-Cl'1l01'0 or 9oz-fiUOIO derivative is employed as starting material.

EXAMPLE XIII 6,9a-difluoro-16a-methyl-A -pregnene-11[3,17u,21-

trial-3,20-di0ne-21-acetaze Approximately 6 g. of anhydrous hydrogen fluoride is passed into a solution of 6-fluoro-9,6,l1Boxido-16u-methyl-M-pregnene-l7u,21-diol-3,20-dione-2l-acetate (5 g.) in redistilled chloroform (100 ml.) contained in a polyethylene bottle at 0 C. The mixture becomes an intense red color and separates into two layers. After 15 hours at 0 C., the mixture is made weakly alkaline by the addition of sodium bicarbonate solution. The chloroform layer is separate and evaporated to dryness to give the crude 6,9a difiuoro-l6a-methyl-A -pregnene-1 1,8,17a,21- triol3,20-dione-2l-acetate. The product is recrystallized from ethyl acetate.

By slight modifications of the above procedure the respective 9a-chloro, and the 9a-bromoderivatives are prepared from HCl and HBr, respectively. The 9&- bromo derivative obtained by this procedure is identical to the 6-fluoro-9ot-bromo-l6a-rnethyl-A -pregnene-115,17a, 2l-triol-3,20-dione-2l-acetates obtained in Example XI.

6,8'-fluoro-9a-bromo-16a-methyl-allopregnane-3-ethylene ketal 17,20;20,21-bismethylenedioxy-3 ,l l-diketo-5a-hydroxy- 6 B-fluoro-9u-methoxy-16a-rnethyl-allopregnane-3- ethylene ketal 17,20 ;20,2 1 -bismethylenedioxy-3, 1 l-diketo-S a-hydroxy- 6,8-fluOrO-9a-ethOXy-16oc-Inethyl-allopregnane-3-etl1ylene ketal EXAMPLE XV 6,9a-difluor0-1 6 u-methy l-A -pregnadi ene-1 711,21- 1 dial-3,11,20-tri0ne A mixture of 0.5 g. of 6,9a-difluoro-16u-methyl-A -pregnene-17a,21-diol-3,11,20-trione-21-acetate, freshly sublimed selenium dioxide (0.5 g.) and 10 m1. of dibutyl cellosolve is heated in a nitrogen atmosphere for about 10 hours at C. The brown supernatant solution is decanted from the residual solid and cooled to room temperature. The addition of low boiling petroleum ether precipitates the impure 6,9a-difluoro-16a-methyl-A -pregnadiene 17a,2l-diol-3,11,20-trione-21-acetate which is purified by chromatographic separation on a Florisil column. Hydrolysis according to the method of Example I gives the corresponding 21-alcohol.

The following A -pregnadienes are prepared in a similar manner: 6-flu-oro-9a-chlor-o-l6a-methy1-A -pregnadiene-17a,2l-

diol-3,11,20-trione 6-fluoro-9a-bromo-16a-methyl-A -p-regnadiene-17u,21-

diol-3,1 1,20-trione 6-fluoro-9a-methoXy-16a-methyl-A -pregnadiene-17a,

21-diol-3,11,20-trione 6-flLlO1'O-9a-chl0TO-l 6u-methyl-A -pregnadiene-1 1p,

17u,21-triol-3,20-dione 1 5 6-fiuor-o-9a-bromo-16a-methyl-A -pregnadiene-1 15,

17a,21-tII01-3 ,ZO-dione 6-fluoro-9wmethoxy- 1 6u-methy1-A -pregnadiene-1 1B,

17u,21-triol-3,20-dione 6,9a-difluoro-1Gwmethyl-N pregnadiene-11fi,17a,2l-

triol- 3 ,ZO-dione 6-fiuoro -9 a-ethoxy-l 6 m-methyl-A -pregnadiene 1 16,

17a,21-triol-3,20-di0ne 6-fluoro-9a-ethoxy-16a-methyl-A -pregnadiene-17a,

21 -dio1-3 ,1 1,20-trione I 6-fluor0-l 6a-methyl-A -pregnadiene-17a,21-diol- 3 ,1 1,20-trione 6-fluoro-16u-methyI-A -pregnadiene-1 1,8,17u,21-

triol-3,20-dione EXAMPLE XVI 6 -flu0r0-] 6 u-methy I-A pregnene-J 1 5,1 70:,21-

trial-3,20-dione-21-acetate Ketal 16 EXAMPLE XVII A solution of 6-fluoro-9B,11B-oxido-lfia-rnethyl-M-pregnene-17u,21-diol-3,20-dione 21-acetate mg.) in methanol (8 ml.) and 72% perchloric acid (0.5 ml.) is held at room temperature for about 3 hours then neutralized with sodium bicarbonate solution and evaporated in vacuo. The product was isolated With chloroform. Reacetylation with acetic anhydride in pyridine gives the corresponding Zl-acetate.

In a similar manner the following 9a-alkoxy compounds are prepared from the proper reactants:

6 fluoro 9u-ethoxy-16a-methyl-A -pregnene-11fi,17a,21-

trio1-3,20-dione EXAMPLE XVIII A variety of 21-esters of the 6-fluoro-16a-methyl corticosteroids of the present invention are prepared in accordance with known procedures using the appropriate 21- alcohol and the proper acylating agent. These include such esters as the formate, the p-ropionate, the isobutyrate, the hexanoate, the octanoate, and the succinate.

The process of this invention is outlined in the following reaction sequence:

O-GH:

CE: I 0

C H2 0 k --G H; Hydrolysis 1 CHO- (3) HOCHaOHaOH (4 NaBHr Ketal (III) (5) RCOOOH (6 CHgSOzCL Pyridine ,Keml

Compounds such as those exemplified in the p rocess out- 20 References Cited by the Examiner UNITED STATES PATENTS lined by Formulae VIII through XIII are useful as inter- 5522552 'g mediates in the preparation of other biologically active 2:838:499 6/1958 spew et aL 26O 239:55 steroids by methods which will be apparent to those skilled 2 341 00 7 195 Hogg et 1 26() 397 45 3nd: art. Some of them, 111 fact, are blOlOglCflllY actlve 25 OTHER REFERENCES What is claimed is: Arth et 31.: 8O J.A.C.S. 3160-62 (1958).

A compound selected from the group consisting of 6B- Bov/Vers et 80 4423 (1958) fluoro 160: methyl-A -pregnene-5a,17a,2l-triol-3,20 LEWIS GOTTS, Primary Examinerdione and its 2l-acetate. 30 L. H; GASTON, E. L. ROBERTS, Examiners. 

